Prenyl Synthase Inhibitors: Novel Anti-Infective Agents

异戊二烯合酶抑制剂：新型抗感染剂

基本信息

批准号：
8532682
负责人：
Eric Oldfield
金额：
$ 33.53万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-06-01 至 2014-09-09
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8532682
关键词：
African Trypanosomiasis Alkanesulfonates Alkynes Amino Acids Anabolism Anti-Infective Agents Antimalarials Bacteria Binding Biological Assay Carotenoids Catabolism Catalysis Cells Chemicals Collaborations Combined Modality Therapy Communicable Diseases Computing Methodologies Confocal Microscopy Crystallography Development Diphosphates Drug Targeting Drug resistance Electron Nuclear Double Resonance Enzyme Inhibition Enzymes Epoxy Compounds Erythrocytes Geranyltranstransferase Grant Growth Inhibitors Hemoglobin Human In Situ Investigation Lead Malaria Methods Monobactams Organometallic Chemistry Oxidoreductase Parasites Pathway interactions Pharmaceutical Preparations Physical condensation Plasmodium Plasmodium falciparum Proteins Protozoa Quantitative Structure-Activity Relationship Quinones Reaction Reactive Oxygen Species Reporting Research Roentgen Rays Route Series Site-Directed Mutagenesis Staging Staphylococcus aureus Structure Testing Tropical Disease Work analog base carboxylate chemical synthesis computational chemistry design enzyme biosynthesis enzyme mechanism fosmidomycin geranylgeranyl diphosphate hemozoin hexokinase high throughput screening in vivo inhibitor/antagonist inorganic phosphate insight interest isopentenyl pyrophosphate isoprenoid killings methicillin resistant Staphylococcus aureus novel novel strategies pathogen phytoene prenyl public health relevance quantum undecaprenyl pyrophosphate synthetase

项目摘要

DESCRIPTION (provided by applicant): The objective of this research is to use a combination of EPR, ENDOR, NMR, X-ray crystallographic, synthetic and computational methods to investigate the structure, function, and inhibition of isoprenoid biosynthesis enzymes of interest as drug targets for treating, primarily, tropical diseases. In Aim 1, we will investigate GcpE, an enzyme involved in isoprenoid biosynthesis in malaria parasites. We hypothesize that its mechanism of action involves unusual metallacycles and that similar metallacycles form with novel alkyne inhibitors. GcpE is an excellent target for the development of novel anti-infectives since it is essential for pathogen survival, is not found in humans, and we have now identified novel inhibitors. In Aim 2 we will carry out a similar series of investigations of the following enzyme (from P. falciparum) in the pathway, LytB, and we hypothesize that because of similarities in their mechanism of action, LytB inhibitors will also inhibit GcpE leading, in cells, to synergistic activity. The third Aim is to develop novel anti-malarials that function by blocking carotenoid and quinone biosynthesis. Carotenoids act to remove reactive oxygen species (ROS, from hemoglobin catabolism) and we hypothesize that carotenoid (and quinone) biosynthesis inhibitors will synergize with current anti-malarials (that enhance ROS formation), reducing drug resistance. The final Aim involves investigation of three other high-value targets: in trypanosomatid parasites, farnesyl diphosphate synthase and hexokinase, in bacteria, undecaprenyl diphosphate synthase. All are essential for survival and sub-micromolar leads have already been identified by us. If successful, the work will provide many new insights into enzyme mechanisms, as well as new drug leads for many global infectious diseases. PUBLIC HEALTH RELEVANCE: This project is aimed at developing new leads for treating infectious diseases, primarily malaria. Focus will be on developing inhibitors for three unique targets in malaria parasites, and on the use of novel drugs against sleeping sickness.

描述（由申请人提供）：这项研究的目的是将EPR，Endor，NMR，X射线晶体学，合成和计算方法的组合研究，以研究类异型生物合成的结构，功能和抑制，主要是治疗的药物，主要是治疗，主要是治疗，主要是热带疾病。在AIM 1中，我们将研究GCPE，GCPE是疟疾寄生虫中涉及类异丙生素生物合成的酶。我们假设它的作用机理涉及异常的金属周，并且具有新型炔烃抑制剂形成类似的金属囊。 GCPE是开发新型抗感染物的绝佳目标，因为它对于病原体生存至关重要，在人类中没有发现，我们现在已经确定了新型抑制剂。在AIM 2中，我们将对LYTB的途径中的以下酶（来自恶性疟原虫）进行类似的研究，我们假设由于其作用机理的相似性，Lytb抑制剂也会抑制细胞中的GCPE引导的GCPE，对细胞，对协同活性。第三个目的是通过阻断类胡萝卜素和喹酮生物合成来开发新型的抗疟疾。类胡萝卜素作用于去除活性氧（ROS，来自血红蛋白分解代谢），我们假设类胡萝卜素（和喹酮）生物合成抑制剂将与当前的抗癌变（增强ROS形成）协同作用，从而减少耐药性。最终目的涉及对其他三个高价值靶标的研究：在细菌中，在锥虫寄生虫，法尼二磷酸合酶和己糖激酶中，未依赖辅导二磷酸合酶。所有这些都是生存至关重要的，我们已经确定了亚微摩尔巨星的铅。如果成功的话，这项工作将为许多全球传染病提供许多新的见解，以及新的药物铅。公共卫生相关性：该项目旨在开发主要治疗传染病（主要是疟疾）的新潜在客户。重点将放在开发疟疾寄生虫三个独特靶标的抑制剂上，以及使用新型药物来抗昏睡病的抑制剂。